Substituted 5,11-dihydro-10,10-dioxodibenzo(c,f)(1,2)thiazepines



United States Patent ABSTRACT OF THE DISCLOSURE The title compounds having Formula I in which Z is an amino nitrogen containing substituent separated from the ring by three carbon atoms are highly active anticholinergic and antihistaminic agents.

FORMULA I R11 9 I I 1 s /S02N 2 r B1 7 5 3 The present invention is concerned with pharmacologically active compounds having the following structural formula and the acid addition salts thereof.

FORMULA I These substances embody the novel heterocyclic nucleus 5,11 dihydro 10,10 dioxodibenzo[c,f][1,2]thiazepine. For convenience in naming the derivatives thereof with which the present invention isconcerned, the ring positions are numbered in Formula I.

The substituent groups represented by R R and R in Formula I may be located in any of the numbered positions of the rings to which they are attached. That is, R may be located in any of the 1-, 2-, 3-, or 4-positions, and R and R may be located in any of the 6-, 7-, 8-, or 9-positions of the thiazepine nucleus.

R is hydrogen, chlorine, bromine, iodine, fluorine, alkyl of 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, etc., or an alkoxy group of 1 to 4 carbon atoms such as methoxy, ethoxy, or butoxy. R and R are hydrogen, chlorine, fluorine, bromine, nitro, methoxy, or methyl. They may be the same or different. R is an alkyl group of from 1 to 4 carbon atoms.

Z is a nitrogen heterocycle doubly bonded through a carbon atom which may be part of the ring or a side chain to the 5-position of the dibenzothiazepine nucleus in 65 3,542,790 Patented Nov. 24, 1970 such fashion that the heterocyclic nitrogen atom is separated from the tricyclic structure by at least 3 carbon atoms. Examples of suitable nitrogen heterocycles include 3-pyrrolidylmethylene, S-thiazolylmethylene, 2-oxazolylethylidene, and 4-piperidylidene.

Alternatively, Z is an aminoalkylidene group of the formula a =AlkN in which Alk is an alkylidene group of from 3 to 5 carbon atoms constituted in such fashion that the substituent is separated from the tricyclic dibenzothiazepine structure by at least 3 carbon atoms. R is an alkyl group of 1 to 4 carbon atoms, and R is hydrogen or an alkyl group of 1 to 4 carbon atoms. Considered as a unit,

may be a nitrogen heterocycle attached to Alk through the nitrogen atom thereof such as pyrrolidino, piperidino, morpholino, thiamorpholino, 4-R -piperazino, etc.

The foregoing substances are basic compounds by virtue of the amino nitrogen atom of the Z substituent. They thus form stable salts with various acids. In view of the pharmacologic activity of the compounds of Formula I, the pharmacologically acceptable acid addition salts are preferred embodiments of the present invention. The pharmacologically acceptable acid addition salts are those in which the anion of the salt does not contribute significantly to the toxicity of the compound as a whole in the doses in which they are administered to achieve te desired parmacological effect. The salts are prepared in conventional fashion by treatment of one of the compounds of Formula I with an acid. For the preparation of salts with mono-basic acids, use of 1 molecular proportion of the two reactants is convenient. In the formation of salts of poly-basic acids, it is convenient to reduce the molecular proportion of the acid so that but one chemical equivalent thereof is employed per chemical equivalent of a compound of Formula I. Generally speaking, the salts are most easily formed by carrying out the reaction in a solvent in which one or preferably both reactants are soluble.

Pharmacologically acceptable acid addition salts may be prepared from the following acids: hydrochloric, hydrobromic, hydroiodic, acetic, propionic, benzoic, phosphoric, nitric. succinic, gluconic, mucic, sulfuric, methanesulfonic, ethanesulfonic, p-toluenesulfonic, citric, tartaric, pamoic, and tannic acids. Others are known to those skilled in the art and may also be employed.

The compounds of Formula I possess central and peripheral anticholinergic and antihistamine activity. Certain members of the series possess substantial antidepressant action. Some have a definite anti-serotonin effect.

To illustrate, 5,11-dihydro--(B-dimethylamino-l-propylidene) 10,10 dioxo 11 methyldibenzo[c,f][l,2] thiazepine (Example 22) and 5,11-dihydro-10,10,dioxo- 5 (1 methyl 4 piperidylidene) 11 methyldibenzo [c,f][1,2]thiazepine (Example 25) exhibit ED values of 1.2 mg./kg. and 0.15 mg./kg. respectively for the antagonism of bronchoconstriction in guinea pigs treated intravenously with a lethal dose of histamine utilizing the method of Lish, et al., J. Pharmacology and Experimental Therapeutics 53, 538 (1966). For comparison purposes, the well-known antihistamine drug diphenhydramine was also tested and found to exhibit ED =0.5 mg./kg.

The former substance (compound of Example 22) also possesses substantial antireserpine action characteristic of that possessed by antidepressant drugs such as imipramine. This test was conducted by administering decreasing doses (25, 12, and 6.5 mg./kg.) of the test compound to separate groups of five mice each intraperitoneally 30 min. before interavenous administration of reserpine, 2 mg./ kg. of body weight. Ptosis was estimated 90 min. after the reserpine dose was administered and the ED value for the prevention of reserpine ptosis was calculated by a standard method. The value 7.75 mg./kg. was Obtained. The well-known antidepressant drug imipramine exhibits ED =4.75 mg./ kg. in this test. 5,11-dihydro-10,10-dioxo- 5-(3-methylamino-l-propyl-idene) 11 -'methyldibenzo- [c,f] [1,2]thiazepine (compound of Example 23) exhibited ED mg./kg. in the prevention of reserpine ptosis.

Compounds of the invention (the products of Examples 22, 23, and 25 were also evaluated in the anti-tremorine test of Everett, et al., Science 124, 79 (1956). According to this test, tremoriue (1,4-dipyrrolidinobut-2-yne) is administered intraperitoneally to mice, resulting in a sustained tremor of the head and limbs, salivation, and lacrimation. Drugs useful in the treatment of Parkinsonism will prevent or abolish the tremors. This is believed to be a central anti-cholinergic effect. Prevention or abolition of salivation and lacrimation by a test drug is a reflection of peripheral anti-cholinergic activity. The results obtained are listed in the following table.

TABLE I.ANTI-TREMORINE ACTION Compound of Compound of Compound of Effect antagonized Ex 22, ED u 1 Ex. 23, ED 1 Ex. 25, ED

Tremor 6. 2-12. 5 6. 2 12. 5 1. 56-3. 13 salivation 3. 0-6. 12 3. 0-6. 12 0. 78-1. 56 Lacrimation 3. 0-6. 12 3. 0-6. 12 0. 780 LD 180 250 110 The compounds of Formula II are required as intermediates for the preparation of the compounds of Formula I. They are prepared as is shown in the diagram for Reactions 1-4. In the diagram the symbols R R R and R have the same meaning as in Formula I.

An R -substituted aniline is acylated with an R R substituted 2-halosulfonylbenzoic acid ester or the corresponding sulfonyl anhydried, as is shown in reaction 1. In the formula, R is a lower alkyl group having up to 5 carbon atoms. X is chlorine, bromine, or iodine. Acylation is completed under usual conditions which preferably employ a basic reaction medium. The Schotten-Baurnann process may be employed, but it is preferred to employ pyridine or other organic base as reaction medium.

The resulting anilide is alkylated in step 2 on the sulfonamide nitrogen atom by treatment in conventional fashion with an R reactive ester such as dimethylsulfate, methyl iodide, butyl bromide, or diethylphosphite, etc. This is preferably accomplished in an inert organic liquid reaction medium such as acetone in the presence of potassium carbonate or equivalent organic base. Alternatively, an R -substituted aniline reactant may be employed in the first step in which event the second step is obviated. This is shown as Step 3.

In either event, the R -substituted sulfonanilide is cyclized in step 4 by hydrolysis of the benzoic ester, conversion thereof to the corresponding benzoyl halide, both according to known methods, and reaction under conditions of the Friedel-Crafts reaction using, for instance, aluminum chloride as catalyst, resulting in ring closure to the product of Formula II. This is represented in step 4. Other methods of cyclization known to the art may be employed in step 4. One such method involves treatment of the sulfamylbenzoic acid with polyphosphoric acid without first forming the benzoyl halide.

REACTIONS 1-4 H R8 R1 s s i 1 KI W? 00 R R co n (3) R 211:.

FORMULA II The 2-sulfo-R R -benzoic acids required to prepare the 2-halosulfony1 benzoate esters employed as starting materials in the foregoing scheme are known to the art. In instances where a specific compound is not available, it may be prepared by known means. This can be accomplished through the following transformations commencing with the correspondingly R R -substituted anthranilic acid, and conversion of the amino group thereof to a halosulfonyl group. Refer to the diagram for Reactions 5-8.

REACTIONS 5-8 R9 a a NH: sn SO:H R R l R l CO2H (5) COzH (6) CO2R S0311 SOzX R R I on CO2R As a first step the selected anthranilic acid is diazotized and the diazonium salt treated with sodium disulfide to produce the corresponding thiolsalicylic acid by known methods. Conditions for this transformation are illustrated in Organic Syntheses, coll. vol. II, p. 580. This is represented in reaction 5. Reaction 6 is an oxidation of the thiol group to a sulfonic acid group. A suitable oxidizing agent is 30% hydrogen peroxide in glacial acetic acid or acetone as solvent. Potassium permanganate, or chromic acid, or other oxidizing agents may also be used. Reaction 7 involves treatment with a halogenating agent conventionally suitable for the transformation of sulfonic and carboxylic acids to the corresponding acid halides such as thionyl chloride, thionyl bromide, PO1 PCl surfuryl chloride, PBr P1 etc. Both the sulfonic acid and carboxylic acid groups are transformed into the corresponding acyl halides. Reaction of the resulting mixed diacyl halide with one molecular proportion of a lower alkanol provides the desired 2-halosulfonyl bcnzoic ester. In the the formulas, for reactions 5-8, R R R and X have the same meanings as previously indicated.

Exemplary of substituted-anthranilic acids suitable for use in the preparation of starting materials according to the foregoing method are:

4-chloroanthranilic acid S-chloroanthranilic acid o-chloroanthranilic acid 4-fiuoroanthranilic acid S-fluoroanthranilic acid S-methylanthranilic acid 5 -methoxyanthranilic acid Another method for the preparation of R R -2-sulfobenzoic acids involves oxidation of correspondingly substituted Z-sulfotoluenes. The oxidation is carried out in conventional fashion using an oxidant such as potassium permanganate, This is represented in reaction 8. The following toluenes may be converted according to this process.

2,3-dichloro-6-sulfotoluene 4-bromo-2-sulfotoluene S-bromo-Z-sulfotoluene 4,S-dibromo-Z-sulfotoluene Other methods are also known for the preparation of the required starting materials.

It will be recognized by those skilled in the art that discretion must be exercised in selecting R -substituted anilines for use in the preparation according to reactions r 1-4 of the R R R R -substituted-5,l1-dihydro-5,10, -trioxodibenzo[c,f]-[l,2]thiazepines of the Formula II. The well-known rules and principles of electrophyllic aromatic substitution are applicable. For example, strongly deactivating R groups may inhibit cyclization and materially reduce the yields obtainable. If an R -substituted aniline reactant is selected in which R is at a position other than ortho to the amino group, cyclization of the resulting sulfonanilide may take place at either of the vacant ortho positions. If these positions are not equivalent, as is the case with a meta substituted aniline reactant, the formation of isomers is a possibility that must be considered. While the formation of isomers does not negate the method as a preparative process it may necessitate a separation of the isomers at some later stage. In many such situations, however, a predominance of one isomer will be obtained so that the method can be applied without substantial difficulty.

The sulfonanilide substituent, of course, is an activating ortho-para directing group which facilitates ring closure as pictured in reaction 4. The directing influence of the R -substituent should be taken into account, preferably so that the directing influence of R and the sulfonanilide group reinforce one another. Nevertheless, in

many instances where R has a conflicting directing influence, the method can still be applied if R is sufliciently weaker in its effect than the sulfonanilide substituent. Fortunately, the effect of the sulfonanilide group frequently overrides the potential antagonistic efiect of many R substituents. Substituted aniline reactants wherein R is a weak m-directing group located in either the ortho or para-positions to the sulfonanilide substituent are generally operable. Preferred R -substituents, although not meeting that description, are the halogens, lower alkyl, and lower alkoxy groups.

The compounds of Formula I are prepared from the compounds of Formula II by reaction of the latter with the Grignard reagent of an aminoalkyl halide or a halogenated nitrogen heterocycle, each having at least 3 carbon atoms separating the halogen atom and the amino nitrogen atom. The chlorides, bromides, and iodides are useful. The Grignard reagent is prepared and reacted under the useful conditions for conducting Grignard reactions. Formation of the reagent from the halide and magnesium turnings may be catalyzed with a crystal of iodine or a few drops of ethyl bromide, if necessary. Anhydrous conditions and inert reaction solvents are employed. Tetrahydrofuran is a particularly preferred solvent for this process.,Elevated temperatures of from 35-150 C. reduce the reaction period, and improve the yields, and are, there fore, preferred. The reflux temperature of the reaction mixture when employing tetrahydrofuran as reaction solvent is quite satisfactory.

Aminoalkyl halides useful in the Grignard synthesis have the formula in which X is chlorine, bromine, or iodine, A is an alkylene group having 3 to 5 carbon atoms with at least three carbon atoms separating X and The carbon atom of A to which X is attached may be a primary or secondary carbon atom, that is it bears at least one hydrogen atom. The R groups may be the same or diiferent but have the same meaning as previously.

considered as a unit may also be a nitrogen heterocycle as previously defined for Specific halogenated nitrogen heterocycles that are useful in the Grignard process are mentioned in the following examples. Refer to Table III.

Hydrolysis of the reaction complex resulting from the Grignard reaction yields the hydroxyl intermediates of Formula III. Slightly acidic aqueous solutions are used for hydrolysis such as aqueous ammonium cholride solution or dilute hydrochloric acid.

FORMULA III The symbols R R R and R in Formula III have the same meaning as previously indicated. The group Y standing in the position occupied by Z in Formula I is a singly bonded substituent rather than a doubly bonded one whose constitution is otherwise the same as is indicated for Z in Formula I, with the further exception that it includes only tertiary amino and heterocyclie types.

The intermediate of Formula III is dehydrated under acidic conditions to provide the product of Formula I. Dehydration is effected by warming this intermediate in solution in the presence of a strong acid. Suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and the organic sulfonic acids such as p-toluenesulfonic acid. Ordinarily an organic solvent is employed. In some instances dehydration takes place spontaneously, while in others an elevated temperature is used to increase the yield and speed of reaction to practical values. In some instances use of a dehydrating agent such as a carboxylic anhydride is preferred. Acetic anhydride is quite suitable in such instances. Other acid anhydrides may, however, be employed. The techniques for effecting dehydrations of this type are well known. To mention a few other dehydrating agents, reference is made to phosphorus oxychloride, phosphorus trichloride, sulfuryl chloride, thionyl chloride, P01 and PO1 The intermediate of Formulas II and III are considered part of the present invention in addition to the pharmacologically active substances of Formula I.

The following examples are provided to specifically illustrate the manner of practicing the invention. They are not to be considered to be the sole embodiments, however, but are provided merely for purposes of illustration.

EXAMPLE 1 5,1 l-dihydro-l1-methyl-5,10,10-trioxodibenzo[c,f] [1,2] thiazepine (a) Methyl 2 (N-methyl-N-phenylsulfamyl)benzoate.A solution of 55 g. of N-methylaniline in ml. of pyridine is treated in dropwise fashion during a period of 30 min. with 118 g. (0.5 mole) of methyl 2-chlorosulfonylbenzoate. External cooling of the reaction vessel and vigorous stirring of the contents is employed. The mixture is heated for 1 hr. at steam bath temperature, cooled, and treated with aqueous 2 N hydrochloride acid. Methyl 2 (N methyl-N-phenylsulfamyl)benzoate precipitates as a crystalline solid which is collected, washed with water, and recrystallized from isopropanol, yield, 125 g.

(b) Z-(N-methyl N-phenylsulfamyl)benzoic acid.- The product of Example 1(a) is dissolved in 500 m1. of ethanol, mixed with a solution of 40 g. of potassium hydroxide in 100 ml. of water, and refluxed for 1 hr. The solvent is removed by distillation and the residue is dissolved in water and acidified with hydrochloric acid. The product separates as an oil which is recovered by extraction with choloroform and the extracts dried 8 over calcium chloride. Evaporation of the solvent at this stage yields -115 g. of 2 (N-methyl-N-phenylsulfamylbenzoic acid as an oil containing some crystalline material. Ordinarily it is preferred not to recover this intermediate but rather to use the dried chloroform solution thereof directly in the following step.

(c) 5,11 dihydro-11-methyl-5,10,10 trioxodibenzo- [c,f][1,2]thiazepine.The chloroform solution of 2- (N-methyl-N-phenylsulfamyl)benzoic acid prepared in the preceding step is refluxed for 2 hrs. with ml. of thionyl chloride. The solvent and excess thionyl chloride are removed by distillation in vacuo (water pump) on the steam bath. The residue is covered with 100 ml. of carbon disulfide and 150 g. of aluminum chloride is added portionwise during a period of 30 min. with stirring and cooling. The mixture is kept for 10 hrs. at room temperature and then heated at reflux for 2 hrs. The supernatant liquid is decanted, the residue treated with ice and hydrochloric acid, and the product recovered by extraction with methylene chloride. The extracts are washed with 2 N hydrochloric acid, water, 10% aqueous sodium carbonate, and finally with water. 5,11-dihydro 11 methyl 5,10,10 trioxodibenzo[c,f][1,2] thiazepine is recovered by evaporation of the solvent and trituration of the residue with ethanol as a light green-colored solid weighing 71 g., M.P. 156 C. The product may be further purified by crystallization from ethanol or acetic acid, but it is satisfactory for use in the following examples without purification.

EXAMPLE 2 Alternative preparation of methyl Z-(N-methyl-N- phenylsulfamyl benzoate Aniline is substituted in chemically equivalent amount for N-methylaniline in Example 1(a). The resulting methyl Z-(N-phenylsulfamyl)benzoate is refluxed in acetone with 1 molecular proportion each of dimethyl sulfate and potassium carbonate for 3 hrs. The product is isolated by filtration and evaporation of the solvent. Application of Examples 1(b) and 1(c) to this product yields the identical product as that obtained in Example 1(c).

EXAMPLES 3-6 Formula II intermediates with various R substituents Substitution of other reactive alkyl esters for dimethyl sulfate in Example 2 such as diethylsulfate (Example 3), ethyliodide (Example 4), butyl bromide (Example 5), and isopropyl chloride (Example 6), and completion of the process as in Examples 1(b) and 1(0) yields corresponding 11-R -5,1O,1O trioxodibenzo[c,f] [1,2] thiazepines in which R is ethyl, n-butyl, or isopropyl.

EXAMPLES 7-20 Formula II intermediates with R, R ring substituents The procedure of Example 1(a) is repeated substituting chemically equivalent quantities of the following methyl R ,R -2-chlorosulfonylbenzoates for the methyl 2-chloro-sulfonylbenzoate specified in that example. The resulting methyl 2 (N methyl-N-phenylsulfamyl)-R benzoates are converted by the method of Examples 1(b) and 1(c) to the desired 5,1l-dihydro-l1-methyl- R,R 5,10,10 trioxodibenzo[c,f] [l,2]thiazepines. The chlorosulfonyl benzoates listed in the following table are prepared from the known sulfobenzoic acids by conversion to the corresponding chlorosulfonylbenzoyl chlorides and reaction with l-molecular proportion of methanol, or alternatively by first esterifying to provide the methyl 2-sulfobenz0ates and then transformation to the sulfonyl chlorides.

TABLE II.EXAMPLES 7-20 [5,1l-dihydro-lLmethyl-R ,R -5,10,10-trixodibenzo[e,fl[1,2]thiazepines] R *,R Starting material substitu nts Example No.:

7 methyl 2-chl0rosulionyl-5-nitrobenzoate 7-n1tr0 8 methyl 2-ehlorosulfonyl-fi-methoxy- 7-metl1oxy benzoate. 9 methyl 3-bromo-2-chlorosulfonyl- Q-bromo benzoate. 10 methyl 2-chlorosulfonyl-3,B-dichloro- 6,9-dichloro benzoate. 11 methyl 2-chlorosulfonyll-nitrobenzoate 8-nitro 12 methyl 5-chl0ro-2-chl0rosulionyl- 7-ehloro benzoate. 13 methyl 6- hloro-Z-chlorosulfonyl- 6-chl0r0 benzoate. l4 n-butyl Z-bromosulionylA-fluoro- 8-fluoro benzoate. 15 ethyl 2 i0dosulfonyl-S-fiuorobenzoate 7-iluor0 l6 isopropyl Z-ehlorosulfonyl-fi-methyl- 7-methyl benzoate. 17 methyl fi-chlorosulionyl-2,3-dichloro- 6,7-tl1chl0ro benzoate. l8 methyl 4-1)rorno2-bromosu1ionyl- S-bromo benzoate. 19 methyl 5-bromo2-bromosull0nyl- 7-br0mo benzoate. 20 ethyl Z-ch1or0sulfonyl-4,5-dibromo- 7,8d1bromo benzoate.

EXAMPLE 21 5,11 dihydro 5 (3-dimethylamino-1-propyl)-10,l0- dioxo-S -hydroxy-1 1-methyldibenzo[c,f] 1,2]th1azep1ne The Grignard reagent is prepared in the usual fashion from 73.2 g. of 3-dimethylamino-1-propyl chloride and 14.4 g. of magnesium turnings employing about 150 ml. of tetrahydrofuran as solvent and small amounts of iodine and ethyl iodide to catalyze the process. The solution of the Grignard reagent is then treated in dropwise fashion with a hot solution of 82 g. (0.3 mole) of 5,11-dihydro- 1l methyl-5,10,10-trioxodibenzo[c,f][1,2]thiazepine in 300 ml. of tetrahydrofuran. The reaction mixture takes on a dark red color. It is refluxed for 3 hrs., cooled, and the reaction complex decomposed by treatment with a solution of 100 g. of ammonium chloride in 3 l. of water. The desired product separates as a solid, which is collected, washed with water, and crystallized from ethanol; yield, 81 g., M.P. 194 C.; ultraviolet absorption maxima of an ethanol solution (C, 0.1 mg./ml.): 276 and 269 m e 1130 and 1400 respectively.

Analysis.--Calcd. for C H N O S (percent): C, 63.58; -H, 6.71; N, 7.76. Found (percent): C, 63.87; H, 6.61; N, 7.86.

EXAMPLE 22 5,11 dihydro-S- 3-dimethylaminol-propylidene) l 0, l0- dioxo-l 1-methyldibenzo[c,f] [1,2] thiazepine The product of Example 21, 70 g., is dissolved in 1400 ml. of ethanol, the solution saturated with dry hydrogen chloride, and refluxed for 4 hrs. The solvent is removed by distillation, yielding the product as a glass-like residue which fails to crystallize when triturated with ether. It is dissolved in water, precipitated as the free base by treatment with sodium hydroxide, and extracted into 'ether. The ether extracts are dried over anhydrous potassium carbonate. The hydrochloride salt is then formed and precipitated by treatment of the solution with anhydrous hydrogen chloride. The somewhat oily solid is dissolved in 200 ml. of hot isopropanol from which the crystalline product separates on cooling. It is twice recrystallized from isopropanol, yielding 21 g. of the desired product, M.P. 1970 C.; ultraviolet absorption maxima (H O, C, 0.01 mg./ml.): 215 mp, e 33,200.

Analysis.Calcd. for C H N -O S-HCl (percent): C, 60.15; H, 6.11; N, 7.39. Found (percent): C, 60.27; H, 6.12; N, 7.44.

10 EXAMPLE 23 5,11 dihydro 10,10-dioxo-5-(3-methylamino-1-propyl-- idene -1 1-methyldibenzo[c,f] [1,2] thiazepine A portion of the hydrochloride salt prepared in Example 22 is converted to the free base as described in that example, and a solution of 2.5 g. thereof in 50 ml. of benzene is prepared. To the benzene solution is added 3 ml.. of ethyl chloroformate and the solution is refluxed for 15 hrs. The cooled reaction mixture is thereafter washed with aqueous 1 N hydrochloric acid and the benzene solution concentrated to dryness in vacuo leaving 1.5 g. of 5-(N-carbethoxy-3-methylamino-l-propylidene)- 5,11 dihydro-10,10-dioxo-1l-methyldibenzo[c,f] [1,2] thiazepine. This material is hydrolyzed and decarboxylated by refluxing with a solution of 1.5 g. of potassium hydroxide in 50 ml. of butanol. A nitrogen atmosphere is maintained throughout the 7 hr. reflux period. The solvent is then removed by distillation and the residue dissolved in ether. The ether solution is extracted with dilute aqueous hydrochloric acid and 5,11-dihydro-10,10-dioxo- 5 (3 methylaminopropylidene) 11 methyldibenzo [c,f][1,2]thiazepine is precipitated as the free base by neutralization of the hydrochloric acid solution with concentrated sodium hydroxide. The base is extracted into ether, the ethereal extract dried over potassium carbonate, and the hydrochloride salt precipitated by treatment of the ether solution with hydrogen chloride, M.P. 240-242 C.; ultraviolet absorption maxima (ethanol C, 0.01 mg./ml.): 242 mu, e 11,000.

Analysis.-Calcd. for C H N O S-HCl (percent): C, 59.14; H, 5.79; N, 7.68. Found (percent): C, 59.19; H, 5.65; N, 7.70.

EXAMPLE 24 5,11 dihydro 10,10 dioxo-5-hydroxy-5-(1-methyl-4- piperidyl) -l l-methyldibenzo [c,f] 1,2] thiazepine The Grignard reagent is prepared from 12.5 g. of lmethyl-4-piperidyl chloride in ml. of anhydrous tetrahydrofuran using 3 g. of magnesium turnings. The reagent is then treated with a solution of 14 g. of ll-methyl- 5,10,10-trioxodibenzo [c,f] [1,2] thiazepine in 50 ml. of anhydrous tetrahydrofuran. The Grignard reaction complex is hydrolyzed in the usual fashion and the resulting carbinol recovered and crystallized from ethanol, M.P. 260 C.

Analysis.-Calcd. for C H N O S (percent): C, 64.49; H, 6.46; N, 7.52. Found (percent): C, 64.66; H, 6.50; N, 7.57. Ultraviolet absorption maxima 278 and 269 m 1: 1050, 62 9 1290 (C, 01 mg./ml. ethanol).

EXAMPLE 25 5,11 dihydro-10,10-dioxo-5-(1-methyl-4-piperidylidine)- 1 l-methyldibenzo [c,f] [1,2] thiazepine The carbinol prepared as described in Example 24, 3 g., is heated for 4 hrs. with 50 ml. of boiling acetic anhydride. The product is isolated and purified by recrystallization from ethanol, M.P. 213 C.

Analysis.Calcd. for C H N O S (percent): C, 67.76; H, 5.68; N, 7.90. Found (percent): C, 67.90; H, 6.27; N, 7.99. Ultraviolet absorption maxima are exhibited at 280 and 249 m e 3640; 6 10,300 (0, 0.01 mg./ml. ethanol).

EXAMPLES 26-35 Products of Formula I with various Z substituents The procedure of Example 21 is repeated substituting the aminoalkyl halides listed in the following table for the 3-dimenthylamino-l-propyl chloride specified in Example 21. The carbinols resulting are then dehydrated according to the method of Example 25 to provide the end prglducts having the structures shown in the following ta e.

TABLE III.-EXAMPLES 26-35 r SOzN Halide reactant Z-substituent Example No.:

26 N,N-dimethyl(5-bromo-1-pentyl)amine (CH3)zNCHzCHzCHgCHgCH= 27 +(3-chloro-1-propyl)-morphollne O NCHzCHgCH:

28 3ehIOrOmethyI-I-methyl-pyrrolidine UCH:

29 5-cl1loromethylthiazolo W 30 N,N-dimethy1(3chloro-1-butyDamine (CH;) N({'JHGH CH= 31 4-(3-chloro-1-propyl)-thiamorpholine S NCH CH OH:

--O 32 2-(2-bromoethyl)oxazo1lne -OH CH= 33 1-(3-ch1oro-1-propyl)-4-methylplperazine CH N jNCHzCHzCH:

34 1-(3-chloro-1-propyl)-pyrro1idino I NCHzCHzCH:

35 1-(3-chloro-1-propyl)-piperidine NCHzCHzCH:

EXAMPLES 36-44 Formula II intermediates with R ring substituents The procedures of Examples L(a), 1(b), and 1(0) are repeated, substituting the anilines listed in Table IV in chemically equivalent amount for the N-methylaniline specified in Example 1(a). The resulting 2-(N-(R -phen- 5O y1)sulfamyl)benzoates are then alkylated on nitrogen by treatment with dimethylsulfate according to the method of Example 2. The products obtained are then cyclized according to Examples 1(b) and 1(c) to yield the intermediates of Formula II which are identified by structure 55 in Table IV.

EXAMPLES 46-63 Products of Formula I with R ,R ,R and various R -substituents The procedures of Examples 21 and 22 are applied to the various R ,R ,R ,R substituted-5,11-dihydr0-5,10,10- trioxodibenz p[c,f][1,2]thiazepines of Examples 3-20 and 36-44 to provide in turn the corresponding R ,R ,R ,R 5,1l-dihydro-S-(3-dimethylaminopropyl) 10,10 dioxo- 5-hydroxydibenzo[c,f][1,2]thiazepines and the dehydration products thereof. The latter are identified in Table V.

TABLE V.EXAMPLES 45-63 [Various R R R", R substituted-5,11-dihydro-5-(3-dimethylaminopropy 'dene)-10,10-dioxodibenz0[c,!][1,2]thlazepincs] Compound Example No.:

45 5,11-dihydro-5 (3-dimethylamino-l-propylidene)-10,10-

di0xo-11-ethyldibenz0[e,f][1,21thiazepine. l1-(n-butyl)-5,11-dihydro-5-(3-dimethylamlno-1-propylidene)-10,10-di0xodibenz0[c,fl[1,2]thiazepine. 5,11-dihydro-5-(3-dimethylaminod-propylidene)-10,10-

di0x011-isopropyldibenzo[c,f][1,2]thiazepine. 5,11-dihydr0-5-(3-dimethylamino-l-propylidene)40,10- dioxo-11-methyl-7-nitrodibenzo[c,i][1,21thiazepine. 49 5,11-(lihydro-5-(3-dimethy1amino-1-pr0pylidene)-10,10-

dioxo-7-methoxy-11-methyldibenzoIe,f][1,2]thiazepino 5O 9-bromo-5,11-dihydro-5-(3-dimethylamino-1-propylidene)-10,10-dioxo11-methyldibenzo[e,f][1,2]thiazepine. 51 6,9-dichloro-5,11-dihydro-5-(3-dimethylamino-l-propylidene)-10,10-dioxo-11-methyldibenz0[c,i][1,2]thiazepine. 62 7-ehloro-5.1l-dlhydro-5'(3-dimethylamlno-l-propy1i dene)-10,10 dioxo-11-methyldibenzo[e,f][1,2]thiazepine. 53 5,ll-dihydro5-(3-din1etl1ylamino-l-propylideneylo (1i0X0-8-lluorO-ll-methyldibeuz0[c,f][1,2]thlazepi 54 5,1l-dihydro5-(3-dimethylamino-l-propylidorm-10 di0x0-7,11-dimethyld1benz0[e,f][l,2]thlazepine.

TABLE V.- Contin ued [Various R R R R -substitu'ted-5, 11-dihydro-5-(3-dimethyl amino propyl) -l0,10-di'ox0dibenzo [mf] 1,21] thiazepines] Compound Example N0.:

56 7,8-dibromo-5,11-dihydro-5-(3-dlmethylamino-l-propylidene)-10,10-dioxo-ll-methyldibenzo[c,f][1,2]- thiazepine.

56 l-bromo-5,11-dihydro-5-(3-dimethylamino-1-propylidene)-10,10-dioxo-11-methyldibenzo[c,i][l,2]thiazepine.

57 5,1l-dihydro-5-(3-dimethylamino-l-propylidene)-10,10-

dioxo-3-iododibenzo-ll-methyl[e,i][l,2]thiazepine.

58 l. 3-chloro-5,11-dihydro-5-(3-dimethylamino-l-propylidene)-10,10-dioxo-1-lmethyldibenzo[c,t][l,2]thiaz epine.

59 5,11-dihydro-5-(3-dimethylamino-l-propylidene)-10,10-

60 2-(n-butoxy)-5,ll-dihydro-S-(3-dimethylamino-1- rpylidene)-10,10-dioxoll-methyldibenzo[e,f][1,2 thiazepine.

61 4-(n-butoxy)-5-11-dihydro-5-(3-dimethylamino-1-propylidene)-10,10-dioxo-11-methyldilaehzo[c,t][1,2]- thiazepine.

62 3-(t-butyl)-5,ll-dihydro-fi-(3-dimethylamino-l-propylidene)-10,10-dioxo-ll-methyldlbenzo[c,t][1,2]thiazepine.

63 5,1l-dihydr0-5-(3-dimethylamino-1-propylidene)40,10-

dioxo-l-fluoro-IO,10-di0x0-11-methyldibenzo[e,i][1,2]- thiazepine.

11 9 R so r no rwherein:

R is located in the 1-, 2-, 3-, or 4-positions and is selected from hydrogen, chlorine, bromine, iodine, fluorine, alkyl of 1 to 4 carbon atoms, and alkoxy of 1 to 4 carbon atoms,

R and R are located in the 6-, 7-, 8-, or 9-positions and are selected from hydrogen, chlorine, fluorine, bromine, nitro, methoxy, and methyl,

R is an alkyl group of 1 to 4 carbon atoms, and

Y is 1-methyl-4-piperidyl, 1-methyl-3-pyrrolidylmethyl,

S-thiozolylmethyl, or 2-oxazolylethyl, or it is a dialkylamino alkylene group of the formula wherein: A is an alkylene group of from 3 to 5 carbon atoms having at least 3 carbon atoms in a straight chain connecting the tricyclic structure to (the dialkylamino group), in which the two R groups are alkyl of l to 4 carbon atoms which may be the same or different, or

considered as a. unit is pyrrolidino, piperidion, morpholino, thiamorpholino, or 4-R -piperazino, and the pharmaceutically acceptable acid addition salts of the foregoing substances.

2. The compound, 5,11 dihydro 5 (3-dimethylamino 1 propyl) 10,10 dioxo 5 hydroxy 11- methyldibenzo [c,f] 1,2]thiazepine.

3. The compound, 5,11 dihydro 10,10 dioxo 5- hydroxy 5 (l methyl 4 piperidyl) l1 methyldibenzo [c,f] 1,2] thiazepine.

4. A compound having the structural formula wherein:

R is located in the 1-, 2-, 3-, or 4-positions and is selected from hydrogen, chlorine, bromine, iodine, fluorine, alkyl of 1 to 4 carbon atoms, and alkoxy of 1 to 4 carbon atoms,

R and R are located in the 6-, 7-, 8-, or 9-positions and are selected from hydrogen, chlorine, fluorine, bromine, nitro, methoxy, and methyl, and

R is a lower alkyl group of 1 to 4 carbon atoms.

5. A compound of claim 4 wherein R R and R are hydrogen, and R is alkyl of 1 to 4 carbon atoms.

6. 5,11 dihydro l1 methyl 5,10,10-trioxodibenzo- [c,f] [l,2]thiazepine.

References Cited UNITED STATES PATENTS 3,247,224 4/1966 Enders et a1 260327 3,274,058 9/ 1966 Weger 260293.44

HENRY R. JILES, Primary Examiner S. D. WINTERS, Assistant Examiner U.S. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N5. 3,542,790 Dated March 23. 1971 Inventofls) Abraham Weber and Jacques Jean Frossard It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 3, line 48, Table I under second "Com ound" column,

oppogit; 'Tremor", "6.2 12.5 should be --6. -l .5--

Column 3, line 50, 0.780" should be (0.078 Column 4, line 27, the line drawn under "R (1300 occurrence which appears in the second line of the formula under the heading "REACTIONS 1-4" should be deleted Column 4, line 42, the legend "FORMULA II" should be spaced to the left under the tricyclic formula Column 4, line 61 under the heading "REACTIONS 5-8",

'CO R" should be CO2 Column 5, line 37, before "toluenes" insert substituted.

Column 6, line 19, "useful" should be usual line 35, change "R to "R line 45, change "R to R Column 7, line 57, before "ml." insert 75 line 63, "hydrochloride" should be hydrochlori Column 8, lines 2 and 3, "(N-methyl-N-phenylsulfamylbenzoic should be (N-methyl-N-phenylsulfamyl)- benzoic (ove Patent No. 3,542,790 Dated March 23, 1971 Column 9, line 71, change "1970" to 197 Column 10, line 71, "dimenthylamino" should be dimethylamino Column 11, in TABLE IV, line 58, "R1" should be R in TABLE IV, line 67, in the subheading, "R

substituent" should be R -substituent in TABLE IV, under the column headed "R substituent", opposite Example No. 44, "3-6-buty1)" should be 3-(t-butyl) Colunm 13, lines 2 and 3 "(3-dimethylaminopropyl)" should be (-dimethylaminopropylidene) continuation of TABLE V, under the heading "Compound", opposite Example No. 58, l0,lO-dioxo-l-methyldibenzo" should be l0,l0-dioxo-ll-methyldibenzo Column 14, claim 1, fourth line from the bottom, "piperidion should be piperidino Under "References Cited", "Weger" should be Weber Signed and sealed this 13th day of July 1971.

(SEAL) Attest:

R LE'ICHER JR. WILLIAM E. SGHUYLER, J E ZE QRiEg Officer Commissioner of Patents 

